Bases genéticas de la discapacidad intelectual y los trastornos del espectro autista: aplicación de las nuevas tecnologías al análisis de variantes del número de copias (CNVs)

La discapacidad intelectual (DI) es un trastorno del neurodesarrollo complejo y fenotípicamente heterogéneo caracterizado por deficiencias significativas en el funcionamiento intelectual y en las habilidades adaptativas de inicio en el período del desarrollo. El trastorno del espectro autista (TEA) es un trastorno del neurodesarrollo caracterizado por deficiencias en las habilidades para la comunicación, en la interacción social y en el desarrollo del lenguaje y por la presencia de intereses restringidos y/o comportamientos estereotipados repetitivos. La etiología de estos trastornos incluye tanto factores ambientales como genéticos, pero una proporción significativa de los pacientes permanece sin un diagnóstico genético definitivo. En este estudio, evaluamos la utilidad de paneles de SNPs del genoma completo de alta densidad en la detección de variantes del número de copias (CNVs) clínicamente relevantes en pacientes con DI y/o TEA. Además, proporcionamos datos moleculares y descripciones clínicas detalladas de pacientes con CNVs patogénicas y/o potencialmente patogénicas

Enhanced localization of genetic samples through linkage-disequilibrium correction

Characterizing the spatial patterns of genetic diversity in human populations has a wide range of applications, from detecting genetic mutations associated with disease to inferring human history. Current approaches, including the widely used principal-component analysis, are not suited for the analysis of linked markers, and local and long-range linkage disequilibrium (LD) can dramatically reduce the accuracy of spatial localization when unaccounted for. To overcome this, we have introduced an approach that performs spatial localization of individuals on the basis of their genetic data and explicitly models LD among markers by using a multivariate normal distribution. By leveraging external reference panels, we derive closed-form solutions to the optimization procedure to achieve a computationally efficient method that can handle large data sets. We validate the method on empirical data from a large sample of European individuals from the POPRES data set, as well as on a large sample of individuals of Spanish ancestry. First, we show that by modeling LD, we achieve accuracy superior to that of existing methods. Importantly, whereas other methods show decreased performance when dense marker panels are used in the inference, our approach improves in accuracy as more markers become available. Second, we show that accurate localization of genetic data can be achieved with only a part of the genome, and this could potentially enable the spatial localization of admixed samples that have a fraction of their genome originating from a given continent. Finally, we demonstrate that our approach is resistant to distortions resulting from long-range LD regions; such distortions can dramatically bias the results when unaccounted for

Patterns of genetic differentiation and the footprints of historical migrations in the Iberian Peninsula

The Iberian Peninsula is linguistically diverse and has a complex demographic history, including a centuries-long period of Muslim rule. Here, we study the fine-scale genetic structure of its population, and the genetic impacts of historical events, leveraging powerful, haplotype-based statistical methods to analyse 1413 individuals from across Spain. We detect extensive fine-scale population structure at extremely fine scales (below 10 Km) in some regions, including Galicia. We identify a major east-west axis of genetic differentiation, and evidence of historical north to south population movement. We find regionally varying fractions of north-west African ancestry (0–11%) in modern-day Iberians, related to an admixture event involving European-like and north-west African-like source populations. We date this event to 860–1120 CE, implying greater genetic impacts in the early half of Muslim rule in Iberia. Together, our results indicate clear genetic impacts of population movements associated with both the Muslim conquest and the subsequent Reconquista.We acknowledge support from the Wellcome Trust (203141/Z/16/Z, 090532/Z/09/Z, 098387/Z/12/Z, 095552/Z/11/Z, 212284/Z/18/Z) and Fondo de Investigación Sanitaria (Grants PI13/01136 and PI16/01057)S

Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study

Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the “Axiom Spanish Biobank” array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10−5, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10−5, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10−5, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10−5, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10−5, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10−2, p = 5.1 × 10−3, p = 1.2 × 10−2, respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory responseThe genotyping service was carried out at CeGen-PRB3-ISCIII; it is supported by grant PT13/0001, ISCIII-SGEFI/FEDERS

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.Fil: Dalmasso, Maria Carolina. Gobierno de la Provincia de la Pampa. Ministerio Publico. Laboratorio de Genetica Forense.; Argentina. Universitat zu Köln; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Confluencia; ArgentinaFil: de Rojas, Itziar. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Moreno Grau, Sonia. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Tesi, Niccolo. Vrije Universiteit Amsterdam; Países Bajos. Delft University of Technology; Países BajosFil: Grenier Boley, Benjamin. Universite Lille; FranciaFil: Andrade, Victor. Universitat zu Köln; Alemania. Universitat Bonn; AlemaniaFil: Pedersen, Nancy L.. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Stringa, Najada. University of Amsterdam; Países BajosFil: Zettergren, Anna. University of Gothenburg; SueciaFil: Hernández, Isabel. Universitat Internacional de Catalunya; España. Instituto de Salud Carlos Iii (isciii); EspañaFil: Montrreal, Laura. Universitat Internacional de Catalunya; EspañaFil: Antúnez, Carmen. Hospital Clínico Universitario Virgen de la Arrixaca; EspañaFil: Antonell, Anna. Universidad de Barcelona; EspañaFil: Tankard, Rick M.. Murdoch University; AustraliaFil: Bis, Joshua C.. University of Washington; Estados UnidosFil: Sims, Rebecca. Cardiff University; Reino UnidoFil: Bellenguez, Céline. Universite Lille; FranciaFil: Quintela, Inés. Universidad de Santiago de Compostela; EspañaFil: González Perez, Antonio. Centro Andaluz de Estudios Bioinformáticos; EspañaFil: Calero, Miguel. Instituto de Salud Carlos Iii (isciii); España. Fundación Reina Sofia; EspañaFil: Franco Macías, Emilio. Universidad de Sevilla; EspañaFil: Macías, Juan. Hospital Universitario de Valme; EspañaFil: Blesa, Rafael. Instituto de Salud Carlos Iii (isciii); España. Universitat Autònoma de Barcelona; EspañaFil: Cervera Carles, Laura. Instituto de Salud Carlos Iii (isciii); España. Universitat Autònoma de Barcelona; EspañaFil: Menéndez González, Manuel. Universidad de Oviedo; EspañaFil: Frank García, Ana. Instituto de Salud Carlos Iii (isciii); España. Universidad Autónoma de Madrid; España. Instituto de Investigacion del Hospital de la Paz.; España. Hospital Universitario La Paz; EspañaFil: Royo, Jose Luís. Universidad de Málaga; EspañaFil: Moreno, Fermin. Instituto de Salud Carlos Iii (isciii); España. Hospital Universitario Donostia; España. Instituto Biodonostia; EspañaFil: Huerto Vilas, Raquel. Hospital Universitari Santa Maria de Lleida; España. Institut de Recerca Biomedica de Lleida; EspañaFil: Baquero, Miquel. Hospital Universitari i Politècnic La Fe; Españ

Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain

Background Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection in children. We aimed to describe the characteristics of children admitted to Pediatric Intensive Care Units (PICUs) presenting with MIS-C in comparison with those admitted with SARS-CoV-2 infection with other features such as COVID-19 pneumonia. Methods A multicentric prospective national registry including 47 PICUs was carried out. Data from children admitted with confirmed SARS-CoV-2 infection or fulfilling MIS-C criteria (with or without SARS-CoV-2 PCR confirmation) were collected. Clinical, laboratory and therapeutic features between MIS-C and non-MIS-C patients were compared. Results Seventy-four children were recruited. Sixty-one percent met MIS-C definition. MIS-C patients were older than non-MIS-C patients (p = 0.002): 9.4 years (IQR 5.5-11.8) vs 3.4 years (IQR 0.4-9.4). A higher proportion of them had no previous medical history of interest (88.2% vs 51.7%, p = 0.005). Non-MIS-C patients presented more frequently with respiratory distress (60.7% vs 13.3%, p < 0.001). MIS-C patients showed higher prevalence of fever (95.6% vs 64.3%, p < 0.001), diarrhea (66.7% vs 11.5%, p < 0.001), vomits (71.1% vs 23.1%, p = 0.001), fatigue (65.9% vs 36%, p = 0.016), shock (84.4% vs 13.8%, p < 0.001) and cardiac dysfunction (53.3% vs 10.3%, p = 0.001). MIS-C group had a lower lymphocyte count (p < 0.001) and LDH (p = 0.001) but higher neutrophil count (p = 0.045), neutrophil/lymphocyte ratio (p < 0.001), C-reactive protein (p < 0.001) and procalcitonin (p < 0.001). Patients in the MIS-C group were less likely to receive invasive ventilation (13.3% vs 41.4%, p = 0.005) but were more often treated with vasoactive drugs (66.7% vs 24.1%, p < 0.001), corticosteroids (80% vs 44.8%, p = 0.003) and immunoglobulins (51.1% vs 6.9%, p < 0.001). Most patients were discharged from PICU by the end of data collection with a median length of stay of 5 days (IQR 2.5-8 days) in the MIS-C group. Three patients died, none of them belonged to the MIS-C group. Conclusions MIS-C seems to be the most frequent presentation among critically ill children with SARS-CoV-2 infection. MIS-C patients are older and usually healthy. They show a higher prevalence of gastrointestinal symptoms and shock and are more likely to receive vasoactive drugs and immunomodulators and less likely to need mechanical ventilation than non-MIS-C patients

Long runs of homozygosity are associated with Alzheimer's disease

Altres ajuts: The Genome Research at Fundació ACE project (GR@ACE) is supported by Fundación bancaria "La Caixa," Grifols SA and Fundació ACE. L.M.R. is supported by Consejería de Salud de la Junta de Andalucía (Grant PI-0001/2017).Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [ β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10 −5 ; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10 −16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10 −4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability

Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain

Background Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection in children. We aimed to describe the characteristics of children admitted to Pediatric Intensive Care Units (PICUs) presenting with MIS-C in comparison with those admitted with SARS-CoV-2 infection with other features such as COVID-19 pneumonia. Methods A multicentric prospective national registry including 47 PICUs was carried out. Data from children admitted with confirmed SARS-CoV-2 infection or fulfilling MIS-C criteria (with or without SARS-CoV-2 PCR confirmation) were collected. Clinical, laboratory and therapeutic features between MIS-C and non-MIS-C patients were compared. Results Seventy-four children were recruited. Sixty-one percent met MIS-C definition. MIS-C patients were older than non-MIS-C patients (p = 0.002): 9.4 years (IQR 5.5–11.8) vs 3.4 years (IQR 0.4–9.4). A higher proportion of them had no previous medical history of interest (88.2% vs 51.7%, p = 0.005). Non-MIS-C patients presented more frequently with respiratory distress (60.7% vs 13.3%, p < 0.001). MIS-C patients showed higher prevalence of fever (95.6% vs 64.3%, p < 0.001), diarrhea (66.7% vs 11.5%, p < 0.001), vomits (71.1% vs 23.1%, p = 0.001), fatigue (65.9% vs 36%, p = 0.016), shock (84.4% vs 13.8%, p < 0.001) and cardiac dysfunction (53.3% vs 10.3%, p = 0.001). MIS-C group had a lower lymphocyte count (p < 0.001) and LDH (p = 0.001) but higher neutrophil count (p = 0.045), neutrophil/lymphocyte ratio (p < 0.001), C-reactive protein (p < 0.001) and procalcitonin (p < 0.001). Patients in the MIS-C group were less likely to receive invasive ventilation (13.3% vs 41.4%, p = 0.005) but were more often treated with vasoactive drugs (66.7% vs 24.1%, p < 0.001), corticosteroids (80% vs 44.8%, p = 0.003) and immunoglobulins (51.1% vs 6.9%, p < 0.001). Most patients were discharged from PICU by the end of data collection with a median length of stay of 5 days (IQR 2.5–8 days) in the MIS-C group. Three patients died, none of them belonged to the MIS-C group. Conclusions MIS-C seems to be the most frequent presentation among critically ill children with SARS-CoV-2 infection. MIS-C patients are older and usually healthy. They show a higher prevalence of gastrointestinal symptoms and shock and are more likely to receive vasoactive drugs and immunomodulators and less likely to need mechanical ventilation than non-MIS-C patients

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.P.G.-G. (Pablo García-González) is supported by CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into ISCIII (Instituto de Salud Carlos III). I.d.R is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A.C. (Amanda Cano) acknowledges the support of the Spanish Ministry of Science, Innovation, and Universities under the grant Juan de la Cierva (FJC2018-036012-I). M.B. (Mercé Boada) and A.R. (Agustín Ruiz) are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE, and CIBERNED. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación—and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de hacer Europa”). Genotyping of the ACE MCI-EADB samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND). Partial funding for open access charge: Universidad de Málag